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P2X receptor

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File:Suramin.svg
purinergic receptor P2X, ligand-gated ion channel, 1
Symbol(s): P2RX1
Locus: 17 p13.3
EC number [1]
EntrezGene 5023
OMIM 600845
RefSeq NM_002558
UniProt P51575
purinergic receptor P2X, ligand-gated ion channel, 2
Symbol(s): P2RX2
Locus: 12 q24.33
EC number [2]
EntrezGene 22953
OMIM 600844
RefSeq XM_001126081
UniProt Q9UBL9
purinergic receptor P2X, ligand-gated ion channel, 3
Symbol(s): P2RX3
Locus: 11 q12
EC number [3]
EntrezGene 5024
OMIM 600843
RefSeq NM_002559
UniProt P56373
purinergic receptor P2X, ligand-gated ion channel, 4
Symbol(s): P2RX4
Locus: 12 q24.32
EC number [4]
EntrezGene 5025
OMIM 600846
RefSeq NM_175567
UniProt Q99571
purinergic receptor P2X, ligand-gated ion channel, 5
Symbol(s): P2RX5
Locus: 17 p13.3
EC number [5]
EntrezGene 5026
OMIM 602836
RefSeq NM_002561
UniProt Q93086
purinergic receptor P2X, ligand-gated ion channel, 7
Symbol(s): P2RX7
Locus: 12 q24
EC number [6]
EntrezGene 5027
OMIM 602566
RefSeq NM_002562
UniProt Q99572
purinergic receptor P2X-like 1, orphan receptor
Symbol(s): P2RXL1
Locus: 22 q11
EC number [7]
EntrezGene 9127
OMIM 608077
RefSeq NM_005446
UniProt O15547

P2X receptors are a family of cation-permeable ligand gated ion channels that open in response to extracellular adenosine 5'-triphosphate (ATP). They belong to a larger family of receptors known as the purinergic receptors. P2X receptors are present in a diverse array of organisms including humans, mouse, rat, rabbit, chicken, zebrafish, bullfrog, fluke, and amoeba.[1]

Basic Structure and NomenclatureEdit

Each functional P2X receptor is a trimer, with the three protein subunits arranged around the ion-permeable pore. To date, seven separate genes coding for P2X subunits have been identified, and referred to as P2X1 through P2X7.[1][2]

The subunits all share a common topology, possessing two plasma membrane spanning domains, a large extracellular loop and intracellular carboxyl and amino termini. With the exception of P2X6, each subunit can readily form a functional homomeric receptor. A P2X receptor made up of only P2X1 subunits is termed a P2X1 receptor. The general consensus is that P2X6 cannot form a functional homomeric receptor when expressed alone, but nevertheless can co-assemble with other subunits to form functional heteromeric receptors. Current data suggests that, with the exception of P2X7, all of the P2X subunits are capable of forming heteromeric P2X receptors with at least one other subunit type. A P2X receptor made up of P2X2 and P2X3 subunits is known as the P2X2/3 receptor.

The relationship between the structure and function of P2X receptors has been the subject of considerable research, and key protein domains responsible for regulating ATP binding, ion permeation, pore dilation and desensitization have been identified.[3][4]

Activation and Channel OpeningEdit

ATP binds to the extracellular loop of the P2X receptor, whereupon it evokes a conformational change in the structure of the ion channel that results in the opening of the ion-permeable pore. This allows cations such as Na+ and Ca2+ to enter the cell, leading to depolarization of the cell membrane and the activation of various Ca2+-sensitive intracellular processes. At least three ATP molecules are required to activate a P2X receptor, suggesting that ATP needs to bind to each of the three subunits in order to open the channel pore. The precise mechanism by which the binding of ATP leads to the opening of the P2X receptor channel pore is not well understood, but is currently under investigation.[3]

PharmacologyEdit

The pharmacology of a given P2X receptor is largely determined by its subunit makeup.[2] For example, P2X1 and P2X3 receptors desensitize rapidly in the continued presence of ATP, whereas the P2X7 receptor channel mostly remains open for as long as ATP is bound to it. The different subunits also exhibit different sensitivities to purinergic agonists such as ATP, α,β-meATP and BzATP; and antagonists such as pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (PPADS) and suramin [1]. Of continuing interest is the fact that some P2X receptors (P2X2, P2X4, human P2X5, and P2X7) exhibit multiple open states in response to ATP, characterized by a time-dependent increase in the permeabilities of large organic ions such as N-methyl-D-glucamine (NMDG+) and nucleotide binding dyes such as propidium iodide (YO-PRO-1). Whether this change in permeability is due to a widening of the P2X receptor channel pore itself or the opening of a separate ion-permeable pore is the subject of continued investigation.

Tissue DistributionEdit

P2X receptors are expressed in cells from a wide variety of animal tissues. On presynaptic and postsynaptic nerve terminals throughout the central, peripheral and autonomic nervous systems, P2X receptors have been shown to modulate synaptic transmission.[1][5] Furthermore, P2X receptors are able to initiate contraction in cells of the heart muscle, skeletal muscle, and various smooth muscle tissues, including that of the vasculature, vas deferens and urinary bladder. P2X receptors are also expressed on leukocytes, including lymphocytes and macrophages, and are present on blood platelets. There is some degree of subtype specificity as to which P2X receptor subtypes are expressed on specific cell types, with P2X1 receptors being particularly prominent in smooth muscle cells, and P2X2 being widespread throughout the autonomic nervous system. However, such trends are very general and there is considerable overlap in subunit distribution, with most cell types expressing more than one subunits. For example, P2X2 and P2X3 subunits are commonly found co-expressed in sensory neurons, where they often co-assemble into functional P2X2/3 receptors.

Physiological RolesEdit

In keeping with their wide distribution throughout the body, P2X receptors are involved in a variety of physiological processes,[1][6] including:

See alsoEdit

Ligand-gated ion channels

External linksEdit

ReferencesEdit

  1. 1.0 1.1 1.2 1.3 1.4 1.5 1.6 North RA (2002). Molecular physiology of P2X receptors. Physiol. Rev. 82 (4): 1013–67.
  2. 2.0 2.1 Gever JR, Cockayne DA, Dillon MP, Burnstock G, Ford AP (2006). Pharmacology of P2X channels. Pflugers Arch. 452 (5): 513–37.
  3. 3.0 3.1 Egan TM, Samways DS, Li Z (2006). Biophysics of P2X receptors. Pflugers Arch. 452 (5): 501–12.
  4. Roberts JA, Vial C, Digby HR, Agboh KC, Wen H, Atterbury-Thomas A, Evans RJ (2006). Molecular properties of P2X receptors. Pflugers Arch. 452 (5): 486–500.
  5. Burnstock G (2000). P2X receptors in sensory neurones. Br J Anaesth 84 (4): 476–88.
  6. Khakh BS, North RA (2006). P2X receptors as cell-surface ATP sensors in health and disease. Nature 442 (7102): 527–32.
  7. Vassort G (2001). Adenosine 5'-triphosphate: a P2-purinergic agonist in the myocardium. Physiol. Rev. 81 (2): 767–806.
  8. Chizh BA, Illes P (2001). P2X receptors and nociception. Pharmacol. Rev. 53 (4): 553–68.


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